Project Summary/Abstract Subpopulations of inhibitory interneurons are hypothesized to control mechanisms of information processing in the brain, such as gain, tuning, normalization, and sensitivity, yet across neural systems, the unique roles of inhibitory cell types remain unclear and largely unstudied. As in all sensory systems, the olfactory bulb must conduct stimulus intensity coding, because without the ability to process odorant intensity, animals are unable to effectively forage, mate, and avoid predation, resulting in decreased survival rates and diluted social interactions. This work expands on previous in vitro experiments and tests predictions from computational neural circuit models for the first time in vivo. New two-photon imaging techniques will be optimized to assess inhibitory (periglomerular) and excitatory (mitral and tufted) cell intensity response functions simultaneously in vivo in the same anesthetized or awake animal and the same glomerulus during stimulation with the same panel of odorants. This new method will reduce data variability that arises when conducting experiments and comparing data across different animals, neural circuits, and odorant stimulations. This proposal will enable direct and novel comparisons across different cell populations. This proposal will also establish the unique roles of two inhibitory interneuron populations (periglomerular and granule cells) in shaping excitatory mitral and tufted cell responses during awake odor intensity dependent processing. Recently published methods for subtype specific expression of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) will be applied in this proposal to manipulate periglomerular and granule cell inhibition in awake mice while they sample odorants varying in intensity. This proposal will elucidate fundamental circuit mechanisms and the roles of inhibitory interneurons used in odor intensity dependent processing in the olfactory bulb.